118 THE ANATOMICAL RECORD (NEW ANAT.) REVIEW Current Concepts of Climbing Fiber Function JAMES R. BLOEDEL AND VLASTISLAV BRACHA This review examines several of the current postulates regarding the function of one of the most intriguing afferent systems in the brain, the climbing fiber system. The fact that these afferents are activated under a variety of conditions has contributed substantially to the diversity of postulates that have been proposed. In part because of the unique anatomical relationship between individual climbing fibers and the dendritic tree of Purkinje cells, these afferents have been proposed as a key input in establishing long-term plastic changes in the cerebellar cortex. This concept is contrasted with other postulates proposing that the heterosynaptic action of this system produces a short-lasting enhancement rather than a long-term depression of Purkinje cell responsiveness. Although a generally accepted view regarding climbing fiber function does not exist, this review emphasizes the extensive functional insights that have been reported and supports the notion that progress toward a complete understanding of these afferents will require an integration of their morphological characteristics with the fundamental physiological properties of their responses assessed in a variety of contexts and conditions. Anat. Rec. (New Anat.) 253:118–126, 1998. ௠ 1998 Wiley-Liss, Inc. KEY WORDS: cerebellum; climbing fiber; cerebellar circuits; Purkinje cells; olivocerebellar Cajal’s elegant description of one of is not graded and which occurs at a tions, Eccles and colleagues (for over- the most unique anatomical relation- relatively low frequency. view, see 1) formulated one of the first ships in the brain, the extensive inter- From the onset of the electrophysi- postulates regarding the functional ac- face between the dendritic tree of a ological studies characterizing the re- tion of this system, the read-out hy- Purkinje cell and a single climbing sponses of Purkinje cells to these in- pothesis. This view proposed that the fiber, triggered a century-long debate puts, the responses evoked by these depolarization evoked by the climbing regarding the function of this unique fibers were found to be as unique as fiber ‘‘read out’’ the level of excitability afferent system. This relationship is their morphology. Primarily as a con- produced via the combined action of illustrated in Figure 1, which also sequence of the classical experiments the mossy fiber–parallel fiber input shows the organization of the other by Eccles, Llinas, and Sasaki (re- directly to Purkinje cells and to the major input to these neurons, the viewed in 1), these afferents were dendrites of the inhibitory interneu- mossy fiber–granule cell–parallel fiber shown to evoke a characteristic, large rons. Although this postulate is no projection. In general, the mossy fiber depolarization of Purkinje cells and an longer considered tenable, it focused input is responsible for modulating associated complex spike response that the attention of physiologists on the unique role these fibers may play in the discharge of Purkinje cells in re- is distinctively different from the ac- regulating the output of the cerebellar sponse to activity in descending path- tion potentials modulated by the other cortex and more generally in regulat- ways as well as to a wide variety of major afferent system to the Purkinje ing the functional properties of the sensory inputs. In contrast, the climb- cell dendrites, the parallel fibers. An cerebellum itself. ing fiber input evokes a response which example of both the intracellularly While not intended to be compre- and extracellularly recorded response hensive, this review will provide an of Purkinje cells to a climbing fiber encapsulation of several theories of input is shown in Figure 2. These climbing fiber function that are rel- responses were produced by stimulat- evant to current discussions regarding Dr. Bloedel is currently the Chair of the ing the cerebellar white matter and this system. Interestingly, none of these Division of Neurobiology at the Barrow consequently contain both an anti- Neurological Institute in Phoenix, AZ. theories have been disproved, and all He and Dr. Bracha, a faculty member in dromically evoked action potential (the have at least some experimental sup- the same Division, codirect a laboratory initial spike in both records evoked by port. Perhaps because critical ques- focused on the learning and control of a variety of movements, with an empha- stimulating the axon of the neuron tions remain unanswered, controversy sis on understanding the role of the in the cerebellar white matter) and still abounds on this topic, contribut- cerebellum in these processes. His fax the complex spike response evoked by ing to the fact that there are almost as number is 602–406–4172; his e-mail ad- dress is [email protected] the climbing fiber input. Based on many viewpoints on this topic as there their electrophysiological observa- are investigators in the field! ௠ 1998 Wiley-Liss, Inc. REVIEW THE ANATOMICAL RECORD (NEW ANAT.) 119 Figure 1. Illustration of the mammalian cerebellar cortex. A single folium is sectioned to reveal the planar organization of the Purkinje cell dendrites, the relationship of the climbing fiber to these structures, the interneurons (basket, Golgi, and stellate cells), and the mossy fiber system. (Reproduced from Bloedel28 with permission of the publisher). SPECIFIC VIEWS OF CLIMBING the body. These experiments as well as flecting a discrepancy or mismatch FIBER FUNCTION earlier electrophysiological studies between the intended and the actual characterizing the inputs to a variety movement. Other proponents of this Climbing Fibers as an Event or of olivocerebellar projections2 led to concept argued that this sensory infor- Error Signal the proposal that the climbing fiber mation is critical to the operation of Several studies in unanesthetized de- may be signaling the occurrence of an the modules consisting of cerebellar cerebrate animals revealed that climb- unexpected sensory stimulus during cortical sagittal zones and the topo- ing fibers were capable of responding the course of a movement. This view graphically organized output from re- to very low intensity stimuli applied to was extended by postulating that these lated regions of the cerebellar nuclei.3 their receptive field on the surface of signals may represent error signals re- At least three lines of experimenta- 120 THE ANATOMICAL RECORD (NEW ANAT.) REVIEW tion in awake behaving animals pro- employed experimental conditions in vide strong evidence supporting the which the animal encountered an un- view that the climbing fiber input can expected sensory input whose charac- signal an unexpected interruption of teristics were difficult to quantify or intended and/or ongoing movement. simply were not measured accurately First, Gellman et al.4 demonstrated as a systematic component of the pro- that olivary neurons (neurons originat- tocol. Simpson and colleagues9 have ing in the inferior olive) that were obviated this problem by employing a highly responsive to low intensity cuta- paradigm in which a very specific, neous stimuli applied passively were quantifiable sensory stimulus was em- not activated when their receptive ployed, this being the movement of fields came in contact with the floor multiple spots of light across the retina during ongoing locomotion. Second, in a specific direction. This visual in- in other experiments,5 climbing fibers put provides a directionally specific were activated by a unique, unex- retinal slip signal which these investi- pected perturbation. Cats were trained gators found to be very effective in to walk on the rungs of a ladder. A activating climbing fiber inputs to spe- rung was permitted to give way unex- cific locations within the cerebellar pectedly when contacted by the cat, flocculus of the rabbit, a region having Figure 2. An extracellularly recorded (A) and numerous interconnections with re- producing a substantial deviation from intracellularly recorded (B) response evoked the expected movement. Under this in two different Purkinje cells by a stimulus gions of the brainstem important in condition, climbing fiber inputs to Pur- applied to the cerebellar white matter (WM). kinje cells were activated. Third, ex- periments in our laboratory employed Together these data multiple single unit recordings from ample, Ojakangas and Ebner8 ob- up to five sagittally oriented Purkinje served that climbing fiber inputs to suggest that this general cells in the intermediate cerebellar Purkinje cells were activated in trials class of events, namely a cortex to examine their responses in which a monkey made errors in when the forelimb of cats and ferrets moving a joystick to a target position mismatch between ambulating encountered a bar inter- after the relationship between the expected and mittently placed in the trajectory of movement of the joystick and the swing phase (reviewed in 6). These movement of the cursor was changed. unexpected behaviors unexpected perturbations were very Together these data suggest that this or external stimuli, is one effective in evoking the synchronous general class of events, namely a mis- activation of climbing fiber inputs to match between expected and unex- condition in which neighboring Purkinje cells within a pected behaviors or external stimuli, climbing fibers frequently sagittal zone. is one condition in which climbing The results of these studies indicate fibers frequently are activated.